The success of antiretroviral therapy (ART) in combating HIV infection has resulted in a dramatic increase in the expected lifespan of HIV-infected patients. An aging population infected with HIV has raised the concern that viral- or viral-associated factors could interact with age-related neuropathologies. Indeed, there is increasing evidence that Alzheimer's disease (AD)-like pathology may be present in some individuals infected with HIV. In particular, there have been repeated observations that pathogenic forms of amyloid (A) accumulate in brains of patients infected with HIV at much higher frequency than is seen in HIV seronegative patients. These observations suggest that there may be some viral- or viral-associated factors that promote abnormal amyloid processing. In preliminary studies we have found that the viral coat protein gp120 can induce activity of secretases involved in the pathogenic processing of amyloid. The experiments outlined in this application are designed to eludicate potential mechanisms by which gp120 may perturb amyloid processing to promote the generation of pathogenic [unreadable]-amyloid peptides. PUBLIC HEALTH RELEVANCE: The success of drug therapies used to combat infection with HIV (the causative virus of Acquired Immunodeficiency Syndrome;AIDS) has dramatically increased the expected lifespan of people infected with HIV. Although neurological complications associated with HIV infection also declined with the advent of drug therapies, an aging population of people infected with HIV has raised the concern that virus- or virus-associated factors could contribute to an increase of Alzheimer's in this population. Indeed, several studies have found evidence for Alzheimer's-like pathology in the brains of people infected with HIV. The studies outlined in this application are designed to determine the mechanisms by which infection with HIV could promotes Alzheimer's-like neuropathology.